Iminomethylindolines

ABSTRACT

This invention relates to a series of 1-iminomethylindolines which are analeptic agents capable of counteracting central nervous system depressant effects of pentobarbital and chloral hydrate. They also exhibit analgesic effects. This invention also relates to a process for the preparation of 1iminomethylindolines which comprises reaction of an indoline with carboxamides selected from the group consisting of amides, lactams, symmetrical or unsymmetrical ureas and hydrazides. Typical examples of 1-iminomethylindoline derivatives are 5acetyl-1-(2-(1-pyrrolinyl)) indoline and 1-(2-(5,5-dimethyl-1pyrrolinyl)) indoline.

United States Patent Wu et al.

[ 1 July 25, 1972 IMINOMETHYLINDOLINES [72] Inventors: Yao llua Wu;Walter G. Lobeck, both of Evansville, Ind.

[73] Assignee: Mead Johnson & Company, Evansville,

Ind.

[22] Filed: Oct. 1, 1969 211 Appl. No.: 862,915

[52] 0.8. CI. ..260/296 B, 260/293.61, 260/294.8 R, 260/3261 1, 260/295S, 424/263, 424/266, 424/274 [51 Int. Cl. ..C07d 31/42 [58] Field ofSearch ..260/326.11, 296.13, 294.8 R, 260/295 S [56] References CitedUNITED STATES PATENTS 2,872,453 2/1959 Jacob et al ..260/293 OTHERPUBLICATIONS Arnol dova et al., Chem. Abstracts, Vol. 66, pages 5081-5082,1tem No. 53, 995-x, (1967).

Primary Examiner-Alan L. Rotman Attorney-Pendleton, Neuman, Williams &Anderson and Robert E. Carnahan 57 ABSTRACT This invention relates to aseries of l-iminomethylindolines which are analeptic agents capable ofcounteracting central nervous system depressant effects of pentobarbitaland chloral hydrate. They also exhibit analgesic effects. This inventionalso relates to a process for the preparation of 1- iminomethylindolineswhich comprises reaction of an indoline with carboxamides selected fromthe group consisting of amides, lactams, symmetrical or unsymmetricalureas and hydrazides. Typical examples of l-iminomethylindolinederivatives are 5-acetyl-1-[2-(1-pyrr0linyl)]indoline and l-[ 2-(5,5-dimethyl-l-pyrrolinyl)]indoline.

12 Claims, No Drawings 1 IMINOMETHYLINDOLINES SUMMARY or THE INVENTIONThe compounds of the present invention relate to liminomethylderivatives of indolines of Formula! and the pharmaceutically acceptableacid addition salts thereof.

lav l-m Formula I These compounds which are new compositions of matterare characterized by Formula I and are useful as analeptic and analgesicagents in mammals.

ln Formula I, the indoline ring positions are numbered to serve as anillustration of the numbering system employed herein for nomenclaturepurposes. The aromatic portion of the indoline ring in Formula I may besubstituted in any of the 4, 5, 6, or 7 positions with an X groupingselected from the group consisting of hydrogen, nitro, amino, R CO,RCONH, and RSO,NH. R substituents represent a lower alkyl group of fromone to four carbon atoms inclusive. The 3 position of the indoline ringmay have R and R substituents independently selected from the groupconsisting of hydrogen and lower alkyl of from one to three carbon atomsinclusive. By independently selected it is meant that the R and Rsubstituents may or may not be identical. An iminomethyl groupingrepresented by the symbol is attached to the 1 position of the indolinering in Formula I. As employed herein the irninomethyl grouping issynonymous with the formimidoyl nomenclature used for this group byChemical Abstracts. In the iminomethyl grouping, R is selected from thegroup consisting of hydrogen, lower alkyl of from one to four carbonatoms inclusive, and RNl-l. In the case of RNH, the R substituent of thel-iminomethyl grouping is selected from the group consisting of loweralkyl of from one to four carbon atoms inclusive, cycloalkyl of fromfour through seven carbon atoms such as cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl. The R substituent is a lower alkyl havingone to four carbon atoms inclusive. Also, R can be pyrrolidinyl,piperdinyl as well as wherein R and R" are lower alkyl groups of l to 4carbon atoms inclusive. In addition, R and R may be joined together toform, in combination with the atoms to which they are each attached anitrogen containing cyclic compound selected from the group consistingof a heteromonocycle and heterobicycle being substituted with zero totwo alkyl groups inclusive having one through four carbon atomsinclusive and having from zero to one additional heteroatom selectedfrom the group consisting of oxygen, nitrogen, and sulfur.

The term lower alkyl" as employed herein includes both straight andbranched chain radicals of the designated number of carbon atoms. Forexample, R in the acyl grouping represented by RCO and in the amidogrouping RCONl-l may be methyl, ethyl, propyl, isopropyl, l-butyl,l-methylpropyl, 2-methylpropyl, tert.-butyl. In the case where the Xsubstituent is R So Nl-l, representative alkanesulfonamido groupings arel-butanesulfonamido, l-methylpropanesulfonamido,tert.-butanesulfonarnido, methanesulfonamido, ethanesulfonamido,l-propanesulfonamido, 2-propanesulfonamido. Alkyl groups which exemplifyR and R substituents are methyl, ethyl, propyl, isopropyl. Inasmuch asthe R and R groupings areindependently selected from the groupconsisting of hydrogen and lower alkyl groupings, they may be identicalor may be any combination thereof.

A particularly preferred embodiment of the present invention comprisescompounds of Formula I, wherein X is located at' the 5 position of theindoline ring and is selected from the group consisting of hydrogen,nitro, and RCO wherein R is a lower alkyl group of from one to fourcarbon atoms inclusive; R and R represent hydrogen; R and R are joinedtogether to form in combination with the atoms to which they are eachattached, a nitrogen containing heteromonocycle having 5 to 7 ringatoms; said heteromonocycle being substituted with zero to two alkylgroups having one to four carbon atoms inelusive; and the non-toxic,pharmaceutically acceptable acid addition salts thereof.

A more limiting and preferred embodiment of the present inventioncomprises the individual compounds 5-acetyl-l-[2-(l-pyrrolinyl)]indoline and l-[2-(5,5-dimethyl-l-pyrrolinyl)] indoline.

The term pharmaceutically acceptable acid addition salts is construed tomean a combination of compounds of the present invention with relativelynon-toxic inorganic and organic acids. In this respect, a variety ofacids may be used and include sulfuric, phosphoric, hydrochloric,hydrobromic, hydroiodic, sulfamic, benzenesulfonic, methane-sulfonic,para-toluenesulfonic, acetic, lactic, succinic, maleic, tartaric,citric, gluconic, ascorbic, benzoic, cinnamic, and related acids.

Conversion of the compounds of the present invention to correspondingpharmaceutically acceptable acid addition salts is accomplished byadmixture of these compounds with substantially one chemical equivalentof any of the various acids hereinbefore defined in an inert organicsolvent such as ethanol, benzene, ethyl acetate, ether, halogenatedhydrocarbon and the like.

For pharmaceutical purposes, the compounds of this invention may beadministered to mammals in the form of the free bases or in the form ofone of their non-toxic acid addition salts. in either form the compoundsof Formula may be compounded and formulated into pharmaceuticalcompositions of unit dosage form suitable for systemic administrationwith organic or inorganic solid materials or liquids which arepharmaceutically acceptable carriers. By systemic administration it ismeant such form of administration as oral, parenteral and rectal.Pharmaceutical compositions considered within the scope of thisinvention may take the form of tablets, powder, granulas, capsules,suspensions, solutions, suppositories, elixirs, ointments and the like.Unit dosage ranging from about 1 to 250 milligrams per kilogram of bodyweight of the mammalian recipient are employed. Appropriatepharmaceutical carriers comprise both solids and liquids such as cornstarch, lactose, calcium phosphate, stearic acid, polyethylene glycol,water, sesame seed oil, peanut oil, propylene glycol, and so on.

Effective analeptic and analgesic responses are induced in mammals whenthe compounds of the present invention are administered systemically inan effective dosage ranging from about I to 250 milligrams per kilogrambody weight of the mammal. Particularly preferred forms of systemicadministration are oral, parenteral, and rectal. Examples of parenteraladministration are intramuscular, intravenous, and subcutaneousadministration. It will be recognized by those skilled in the art thatthe dosage of the compounds of the present invention will vary with theform and mode of administration and to some degree with the particularcompound chosen. it will generally be found that when a compound of thepresent invention is administered orally, a larger quantity of theactive agent is required to produce the same effect as a smallerquantity thereof given parenterally. In general, the compounds of thisinvention are most desirably administered at a concentration level thatwill generally afford effective results without causing any harmful ordeleterious side effects. A dosage level that is in the range of fromabout 2.5 to mg./kg. of body weight of the mammalian species treated perday is most preferred in order to achieve effective results.

The compounds of the present invention which are represented by FormulaIV are prepared by reaction of a substituted indoline of Formula II witha carboxamide of Formula III in the presence of phosphorus oxychlorideas illustrated in the following equation.

8 P001: Y R R CNHR 3:

\N N H LR Formula II Formula III Formula IV In Formulas II, III, and IV,R, R, R and R have the meanings hereinabove given for Formula I. The Ysubstituent is selected from the group consisting of hydrogen, nitro andFCO wherein R represents a lower alkyl group of from one to four carbonatoms inclusive. Carboxarnides of Formula Ill are comprised of amides,lactams, symmetrical and unsymmetrical ureas, or hydrazides.

In carrying out the process of this invention for the preparation ofFormula IV compounds approximately equivalent molar quantities of thereactants (indoline and the appropriate carboxamide) and phosphorusoxychloride are dissolved or suspended in an inert solvent. A preferredsolvent for carrying out the process is 1,2-dichloroethane, although itmay be carried out with other inert solvents such as chloroform, carbontetrachloride, l,l-dichloroethane, benzene, toluene, hexane, and thelike. The mode of addition of the reactants is not critical in carryingout the hereinabove described process. For example, a solution orsuspension of an indoline and a carboxamide can be added to a solutionof phosphorus oxychloride or the sequence of addition may be reversedand a solution of phosphorus oxychloride can be added to a solution orsuspension of the carboxamide and amine. Alternatively, phosphorusoxychloride can be first added to the amine and the carboxamide thenadded or the phosphorus oxychloride can be added to the carboxamide andthis mixture then combined with the amine. Combination of the reactantsprovides an exothermic reaction and accordingly external cooling isemployed in some instance to moderate the reaction. The reaction takesplace in a facile manner when the reactants are combined and generallydoes not require prolonged reactionperiods for completion and formationof an indoline l-iminomethyl derivative of Formula IV. Generally it ispreferred to carry out the reaction with efficient stirring and forperiods ranging from about I to 18 hours. Reaction may be carried out attemperatures of about 35 C. to 100 C. However, for ease of laboratoryoperation, it is preferred to carry out the combination of the reactantsat room temperature and to then stir the reaction mixture overnightbefore isolating the product. In some instances, where the carboxamidehas only limited solubility in the reaction solvent, the reaction iscarried out at refluxing temperature of the inert solvent. For example,l-[2- (5,5-dimethyl-l-pyrrolinyl)]indoline is obtained by refluxing amixture of 5,S-dimethyl-Z-pyrrolidinone suspended in 1,2- dichloroethanecontaining phosphorus oxychloride and indoline.

The compounds of Formula I wherein the X substituent is amino, RCONH orR'SO,NI-I are synthesized by an alternate process. This processcomprises reduction of compounds of Formula IV wherein the Y substituentis nitro to the corresponding amino derivatives by standard catalytic orchemical procedures well known to the art. The amino derivatives ofFormula I, wherein X is NIL, may then be reacted with loweralkylsulfonyl chlorides or lower alkyoyl halides or their respectiveanhydrides'to provide compounds of Formula I wherein X is RCONI-I andRSO,NI-I.

PHARMACOLOGY The compounds of the present invention effectivelystimulate the central nervous systcm of mammals. Compounds havingbiolop'cal activity of this type are generally referred to as beinganaleptic agents. Analeptic activity can be demon- LII LII

tral nervous system depression produced by administration ofpentobarbital to cats or chloral hydrate to mice.

The pentobarbital antagonism test for the compounds of the presentinvention in the cat is carried out in the following fashion. A eat ofeither sex wherein a chronically indwelling intravenous cannula has beenpreviously surgically inserted, is placed in an observation cubiclemeasuring 2 X 2 X 2feet. The cat is allowed to move about freely at theend of a leash. A dose of 12 milligrams per kilogram of body weight ofpentobarbital sodium in aqueous solution is infused at the rate ofapproximately 2 milligrams per kilogram per minute via tubing containedin the leash. One-half hour after the start of this infusion the cat isin a state of light anesthesia characterized by unconsciousness,immobility, relaxed nictating membrane, and is not responsive tohandling but has active pinneal, palpebral and paw-pinch withdrawalreflexes. At this time the liminomethylindoline compound is infused inconcentration of 10 milligrams per milliter at a rate of 0.2 millitersper minute until (a) consciousness is restored, (b) a total of 25milligrams per kilogram of body weight of test compound is administeredor (c) mounting toxicity interfers. Consciousness is recognized by thepresence of alertness to surroundings as indicated by the ability of thecats eyes to follow a movement of a nearby object and in its attempts toassume an upright position.

Representative compounds of the present invention wherein a dose of upto 25 milligrams per kilogram of body weight restored consciousness topentobarbital treated cats TABLEI Chloral Hydrate Antagonism in theMouse Example Per Cent Reduction Number in Sleeping Time at (Table III)20 mg/kg Body Weight 2 38 3 24 4 24 7 l0 8 36 9 65 I7 62- l8 I7 21 50 Ina number of instances, analeptic activity as shown by ant'agonism topentobarbital hypnosis in the cat and chloral hydrate antagonism in themouse of the present compounds of this invention are equal to orcomparative with known central nervous system stimulant agents. Forexample, 4-ethyl-4- methyl-2,6-piperidinedione (The Merck Index, 8thEdition, page 124), a well known analeptic agent, reduces by 50 percentthe sleeping time caused by the administration of a 300 milligram perkilogram of body weight of chloral hydrate to the mouse at a dose of14.4 milligrams per kilogram body weight. In a comparative test two ofthe preferred compounds of the present invention,1-[2-(5,5-dimethyl-l-pyrrolinyl)] indoline hydrochloride and5-acetyl-l-{2-(1-pyrrolinyl)] indoline, produce a 50 percent reductionof the sleeping time at doses of IS and 10 milligrams per kilogram ofbody weight respectively. Comparison of pentobarbital antagonism in catsindicates that 4-ethyl-4-methyl-2,6-piperidinedione and theaforementioned preferred compounds are substantially equiactive inrestoring consciousness to a pentobarbital treated cat.

The activity cage technique described by J. W. Kissel, Science, 139,I224 (1963), was used to measure motor stimulation in rats. In thistest, compounds of the present invention a: m such the analepticagentsl-[2-(5,5-d1methyl-l-pyrrohnyl)] Q g a g g g indoline hydrochloride and5-acetyl-1-[2-(l-pyrrohnyl)]mg e g re g g-g e q g qg egg doline, did notproduce an increase in motor activity. The g i l 2i 3fi 3fi3 a" 3i.absence of motor activity exhibited by these compounds 5 t demonstratesthat analeptic action may be present without *3 2 3E 2.5: g concomitantmotor stimulation. Since motor stimulation is 5 ,;;'15:;,;3' .4;generally associated with analeptic action, the instant compounds ofthis invention are unique in the respect that while Eg 3): 1"12 1 {i 31,$12912: 11 1i; they are analeptic agents they are not motor stimulants.g b 5 3 1 e3 352 3 13 c'azpmcna bwmegmwwwv-tqwmlbahqtbc ,w In additionto having analepuc activity, compounds of For- HE bi oi oi oi oi m oi =6oi mula I are active agents in preventing the phenylquinone 5 g g i g g352 3 writhing syndrome in mice. The prevention of this syndrome is g] g5-; f '3] 3 employed as a measure of analgesic activity l-lendershot andm N N Forsaith, J. Pharmacol. Exp. Therap. I25, 237 (1959). In this 15 gz '1 test, groups of 10 to mice are injected subcutaneously with & I H Ng graduated doses of the test compound. At the time of a m 3 Epredetermined peak effect, the animals are administered a dose of 2.5milligrams per kilogram of body weight of phen- 20 a O 8i z; ylquinoneintraperitoneally. The latter injection induces E. S g g e E g 3 8 '5writhing episodes in the mice. The number of such episodes 3 6 g 5 g f gg; g g 3 exhibited by each mouse during the 10 minute period followq E'5; 3' mg in ection is counted and the average percent of decrease in 8Z a g g 8 g a as t the number of episodes as compared to a control groupof g mice is recorded for each dose of test compounds. A log dose- E Z Z2 2 z 3 response curve is prepared and the dose of the test compound a mrequired to decrease the number of writhing episodes of 50 percent isestimated by interpolation. Results relating to a O 8 8 E as i1 8 numberof compounds of the present invention compared to E5 5 g 33 E g 3 3 2;aspirin are listed in Table II. a 5 E E 5 E a 5 H s o o TABLE 11 g s 5 E5 3 5 E i a Q is 'a; g 1 E a g Prevention of Phenylqulnone writhing E aE E g a g. g E ,3 ,3 Ex. No. 51),, a 6% E E i E 5 (Table IV) mg/kg bodyweight 2 AA. 5 B 2 a 2: g Q 2 s z a e 2; g a: N 2 e N a N 3 15.8 E E 73.85 .1. 1 as 2 l e e 13. E ee'g'sggg a i; ii; 52 a fasiaa 33 o E o H I:h E 33 'i seE-siz 13 1612 g 19 10.3 En g E 2:; Z; a g s E e "i 1"DESCRIPTION OF THE PREFERRED EMBODIMENTS 5 E i E 5 The followingexamples are intended to illustrate the present invention withoutlimiting it thereto. 2 E Examples 1-21. General Procedure for thePreparation of 1- i ,g '3 "l "i "1 Iminomethylindolines.- A mixture ofequimolar amounts of 55 1 ,5 E E E E E 5 E 5 an indoline and theappropriate carboxamide in 1,2- 2 dichloroethane (250 ml. per 0.1 moleof reactant) is treated 6 E dropwise with an equimolar solution ofphosphorus oxi i Q E. g E, j: ychloride in a 1,2-dichloroethane (50 ml.per 0.1 mole of g i g g E g E reactant) over a period of 30 minutes to 1hour at 20-30 C. j g, i g :g g The mixture is stirred overnight and thenpoured into crushed g .5 I; E E g E m "a e e e a 5 a The dichlorethanelayer is separated from the aqueous layer T i E: g f1 =3 5; g an dextracted with dilute hydrochloric acid. A 20 percent 65 E g E g :2 asodium hydroxide solution is added to the dilute acid solution E E. .2;5 3 g a providing an oil or a precipitate which is taken up in ether. 5Ear g 5 i E g- Concentration of the ethereal extract provides the crudeE "5,3 g 2 5:5 5; 5- product which is purified by standard organicprocedures well a i=5 $58: g 5'? gi g g known to those skilled in theart such as by crystallization, g1 g5 5g 5g Z Ea "i5 5 5 5-5distillation, or preparation of a suitable acid addition salt. 2 #5 3% F5 $5 31 The following tabulation is illustrative of a number of l- "j "j"f "j "f "I iminomethylindolines of the present invention prepared by EE E E Z i E E 5 following the hereinabove described procedure.Purification i E E 5 i 5 E i E E solvents, melting points, analyticaldata and infrared absorp- 5g 5 i E E E i E E 3 tion spectrum are alsoprovided in Table III. 5% g j 5 ,i

Example 22. -Amino-l-[2-(1-pyrrolinyl)]indoline. A solution of 1-[2-(l-pyrrolinyl)]-5-nitroidoline (8 g. 0.03 mole) in 200 ml. of 0.15 Nhydrochloric acid is reduced on a Parr hydrogenator employing 1 teaspoonof W-60 Raney Nickel catalyst. When the hydrogen uptake ceases thecatalyst is collected and the filtrate is made basic with percentpotassium hydroxide solution which provides a precipitate of the freeamine. The precipitate is taken up in 50 ml. of acetone, treated withdecolorizing charcoal and concentrated to about 20 ml. On standing, theacetone solution deposits 1.6 g. (27 percent) of l-[2-(l-pyrrolinyl)]-5aminoidoline, m.p. l74-l 76.5 C.

Analysis. Calcd. for C l-l m: C, 71.61; H, 7.51; N, 20.88. Found: C,71.46; H, 7.76; N, 20.59. Example 23.5-Methanesulfonamido-l-[2-(l-pyrrolinyl)]-indoline.-

An equimolar portion of methanesulfonyl chloride is added to5-amino-l-[2-( l-pyrrolinyl)]indoline in pyridine. After stir- .ring themixture overnight the product is isolated by quenching the pyridinesolution in water and collecting the precipitated5-methanesulfonamido-l-[2-(l-pyrrolinyl)]indoline. Alternatively, theproduct may be recovered by extraction with a water immiscible organicsolvent such as ether,

benzene, ethyl acetate and the like.

TABLE IV.-ADDITIONAL l-IMINQMETHYLINDOLINES Product 53533 X R R YStarting materials H H CH: 7 3-methylindoline and 2-pyrrolidinone.

26 H H 2115 Ha B-ethylindoline and N-methylacetamide.

NCH;

27 H H CH(CHa)z 3-isopropylindoline and 5,5-dimethyl-2-pyrrolidinone.

kCH: \N CH:

28 H C C 3,3-dimethyllndo1ine and 5,5-dimethy1-2-pyrrolidinone.

k N CH3 29 H n-CaH1 -n- :H1 3,3-dipropylindoline and Z-pyrrolidinone.

30 5-N0z H H fi-nitroindoline and 2-azabicycloI2-2-2]octan-3one.

31 S-NO; H H G-nitroindoline and 5,5-dimethyl-2-pyrrolidinone.

CHa

N CH:

32 5-N0z CH3 CH3 3,3-dimethyl-5-nitroindoline and 5,5-dimethyl-2- CH3pyrrolldinone.

N CH:

33 B-NHz H H 0 G-nitroindollne and 3-ketomorphollne.

34 5'n-C4HISO2NH CH; CH;; 3,3-dimethyl-5-nitroindoline andZ-pyrrolidlnone.

35 0 CH: CH; 3,3-dirnethyl-5-acetylindoline and 2-pyrrolidin0n ll 5-CH3CProduct 53% x m R: Y Starting 11180611818 86 H H H CH Indoline andN-cyclobutylformami 31 H H 11 :i-n-C;H Indoline and N-cyelohepthlb ym asn H H c-NHcH oH, Indoline and N,N'-diisop n l CH( t)z s9 n H H -CNHCH;Indoline and N-isopropyl-N- I C H (C Hg): 40 3 H H c c Indoline andl-acetyl-Z-methylJ-D p n-CaH1 41 H H H on, Indoline and 4-methy1-2-pyr42 H H H CH; Indoline and 3-methy1-2-pyrrolldlnone.

N I 0 H H fi-butyrylindollne and 5,5-dimethyl-2-pyrrolldlnone.

(hi-OM11 v CHs 44 0 H H fi-lsobutyryllndoline and Z-pyrrolidlnone.

IS-(CHmCH 46 0 H H G-acetylindollne and 2-pyrrolidlnone. o-cmi':

46 0 H H fi-nitroindollne and 5,5-dimethyl-2-pyrrolldinone. s-cmiinn kH3 f on,

47--.; O H H fi-nitroindoline and 2-pyrrolidiuone.

G-CHI NH J 48 H H j fi-nltroiudoline and Z-pyrrolidinone.

Example 49 Tablets.- The iminomethylindolines compounds of the presentinvention are compounded into tablets according to the followingexample.

Material jection, USP. The solution is adjusted to pH 4.2 with 0.1 Nsodium hydroxide. The solution is sterilized by passage l-[2-(5,$-dimethyl-l-pyrrolinyl)] indoline hydrochloride Magnesium stearateCorn starch Corn starch pregelatinized Lactose gredient.

' The foregoing materials are blended in a twin-shell blender and thengranulated and pressed into tablets weighing 250 mg. 70

each. Each tablet contains 50 mg. of active ingredient.

Example S0. Solution for Parenteral lnjection.- The liminomethylindolinecompounds of the present invention are formulated for parenteraladministration according to the following example. A sterile solutionsuitable for intravenous in- 60 through a bacteriological filter andaseptically filled into 10 ml. glass ampoules, each ampoule contains'50mg. of active in- What is claimed is: l. A compound selected from thegroup consisting of indoline derivatives having the formula and thepharmaceutically acceptable acid addition salts thereof wherein X islocated in any of the 4, 5, 6, or 7 positions of the indoline ring andis selected from the group consisting of hydrogen, nitro, amino, andR'CO wherein R is a lower alkyl group of one to four carbon atoms,

R and R are independently selected from the group consisting ofhydrogen, and lower alkyl of one to three carbon atoms inclusive and Rand R together with the iminomethyl group to which they are attachedform a pyrroline, 3,4,5,6- tetrahydropyn'dine, or3,4,5,6-tetrahydroazepine ring wherein each of said pyrroline, 3,4,5,6-tetrahydropyridine, and 3,4,5,6-tetrahydroazepine rings is unsubstitutedor substituted with up to 2 alkyl groups having one to four carbon atomsinclusive.

2. The compound selected from the group consisting of indolinederivatives having the formula 4 1L1 and the pharmaceutically acceptableacid addition salts thereof wherein X is RCO; R is a lower alkyl groupof one to four carbon atoms inclusive; R and R" are hydrogen and R and Rjoined together fon'n a pyrroline ring.

31 The compound selected ribm the group consisting of indolinederivatives having the formula t r-um:

2. The compound selected from the group consisting of indolinederivatives having the formula
 3. The compound selected from the groupconsisting of indoline derivatives having the formula 4.5-Acetyl-1-(2-(1-pyrrolinyl))indoline. 5.1-(2-(5,5-Dimethyl-1-pyrrolinyl))indoline. 6.1-(2-(5,5-Dimethyl-1-pyrrolinyl))indoline hydrochloride. 7.1-(2-(1-Pyrrolinyl))indoline.
 8. 1-(2-(1-Pyrrolinyl))indolinehydrochloride.
 9. 1-(3,4,5,6-Tetrahydro-2-pyridyl)indoline. 10.1-(3,4,5,6-Tetrahydro-2-pyridyl)indoline hydrochloride. 11.5-Nitro-1-(2-(1-pyrrolinyl))indoline. 12.5-Nitro-1-(2-(1-pyrrolinyl))indoline hydrochloride.